Infectious bioterrorism agents such as smallpox and anthrax represent a critical public health concern. Important goals of biodefense research include the development of predictors of pathogenicity of bioterrorism agents for rapid response and the prediction of clinical outcomes such as adverse events following vaccination. Our success in these biodefense endeavors will depend critically on the bioinformatics methods and software that are available for making sense of high-dimensional data generated by technologies such as DNA microarrays and mass spectrometry. The goal of this research program is to continue the development, evaluation, distribution and support of our successful open-source Multifactor Dimensionality Reduction (MDR) software package for identifying combinations of genetic and environmental predictors of clinically important biodefense outcomes. We will first evaluate new methods from our research group and those that have been proposed by other research groups and assess the best approaches for inclusion in new versions of the MDR software (AIM 1). The inclusion of new methods such as stochastic search algorithms for genome-wide analysis and linear models for continuous endpoints will ensure that the MDR software stays on the cutting edge. Second, we propose to develop a web server that biodefense researchers can use as a source of expert knowledge in the form of gene weights that are generated from biochemical pathways, Gene Ontology (GO), chromosomal location and protein-protein interactions, for example (AIM 2). Expert knowledge files generated by the web server will be used by the MDR software to prioritize single nucleotide polymorphisms (SNPs) for interaction analysis in genome-wide association studies or GWAS. These additions will ensure that MDR is ready for application to GWAS that are now commonplace. We will then apply these methods to GWAS data from an ongoing study of adverse events following vaccination for smallpox (AIM 3). Finally, we will identify opportunities to address other important bioterrorism research questions with our software that are consistent with the research objectives of the NIAID/NIH (AIM 4). All bioinformatics methods and tools will be provided in a timely manner for free as open-source software.